Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A heptadecapeptide was identified and purified from porcine brain tissue as a ligand for an orphan heterotrimeric GTP-binding protein (G protein)-coupled receptor (LC132) that is similar in sequence to opioid receptors. This peptide, orphanin FQ, has a primary structure reminiscent of that of opioid peptides. Nanomolar concentrations of orphanin FQ inhibited forskolin-stimulated adenylyl cyclase activity in cells transfected with LC132. This inhibitory activity was not affected by the addition of opioid ligands, nor did the peptide activate opioid receptors. Orphanin FQ bound to its receptor in a saturable manner and with high affinity. When injected intracerebroventricularly into mice, orphanin FQ caused a decrease in locomotor activity but did not induce analgesia in the hot-plate test. However, the peptide produced hyperalgesia in the tail-flick assay. Thus, orphanin FQ may act as a transmitter in the brain by modulating nociceptive and locomotor behavior.
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PMID:Orphanin FQ: a neuropeptide that activates an opioidlike G protein-coupled receptor. 748 66

Orphanin FQ, also known as nociceptin, is a heptadecapeptide with very high affinity for a novel member of the cloned opioid receptor family which produces hyperalgesia in mice. In addition to hyperalgesia, which is observed soon after administration of orphanin FQ, we now describe a delayed analgesic response. Unlike orphanin FQ-induced hyperalgesia, orphanin FQ-induced analgesia is readily reversed by the opioid antagonist naloxone, implying an opioid mechanism of action. In view of the very poor affinity of orphanin FQ for all the known traditional opioid receptors and the low affinity of opioids for the 125I[Tyr14]orphanin FQ binding site, orphanin FQ-induced analgesia is probably mediated through a novel orphanin FQ receptor subtype.
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PMID:Naloxone sensitive orphanin FQ-induced analgesia in mice. 889 15

The influence of orphanin FQ (OFQ) (a newly discovered 17-amino acid peptide) on acupuncture analgesia (AA) was assessed in rat tail-flick model. Intracerebroventricular (i.c.v.) injection of OFQ (1 microgram) elicited a significant decrement of pain threshold which was abolished by the repeated pretreatment with antisense oligonucleotide (ASO) to OFQ receptor. Electroacupuncture (EA) induced an obvious analgesic effect; when OFQ was used combined with EA, it showed a dose-dependent effect on antagonizing the EA analgesia. When rat was repeatedly i.c.v. injected with ASO to block the synthesis of OFQ receptor, the EA analgesia was enhanced markedly. In this instance, the OFQ did not show antagonistic effect on EA analgesia any more. The results suggest that the OFQ play its antagonistic role on EA analgesia via activating OFQ receptor.
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PMID:Antagonistic action of orphanin FQ on acupuncture analgesia in rat brain. 905 Nov 67

1. The present study was designed to investigate further the effects of the newly discovered orphanin FQ (OFQ)-the endogenous ligand for the orphan opioid receptor (called, e.g., ORL, and LC132)-on pain modulation in the rat. We used the tail-flick assay as a nociceptive index. 2. When injected into a cerebral ventricle, OFQ (4 fmol-10 nmol) has no effect on basal tail-flick latency by itself at any dose, but dose-dependently antagonizes systemic morphine analgesia (400 fmol 50 nmol). 3. Injected intrathecally, OFQ (3 and 10 nmol) displayed an analgesic effect without producing motor dysfunction, and potentiated morphine analgesia (1 and 10 nmol). 4. The anti-opioid effect of OFQ in rat brain and the high level of expression of LC132/ORL, receptor in the locus coeruleus indicated a possible role of OFQ in the precipitation of opiate withdrawal symptoms. However, no such precipitation was observed by OFQ in morphine-dependent rats.
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PMID:Bidirectional modulatory effect of orphanin FQ on morphine-induced analgesia: antagonism in brain and potentiation in spinal cord of the rat. 905 7

Recent studies suggest that the novel opioid peptide orphanin FQ (OFQ) is involved in pain modulation. We found that intracerebroventricular (i.c.v.) administration of OFQ in the rat produced a dose-dependent antagonism of the analgesia induced by 100 Hz electroacupuncture (EA) stimulation as measured in the radiant heat tail-flick assay. Antisense oligonucleotides injected i.c.v. potentiated EA analgesia, presumably by interfering with the expression of the OFQ receptor in brain. These results suggest that endogenous OFQ exerts a tonic antagonistic effect on EA-induced analgesia. No such antagonism was observed when OFQ was injected intrathecally (i.t.). Rather, it appears that spinal OFQ produced a marked analgesic effect and enhanced EA-induced analgesia. These findings are consistent with the experimental results obtained in rats where morphine-induced analgesia is antagonized by i.c.v. OFQ and potentiated by i.t. OFQ.
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PMID:Involvement of endogenous orphanin FQ in electroacupuncture-induced analgesia. 908 Apr 36

Previous work reveals that orphanin FQ/nociceptin (OFQ/N) administered supraspinally produces an initial hyperalgesic response followed by analgesia. Spinally, OFQ/N elicits a rapidly appearing, naltrexone-reversible, dose-dependent analgesia in the tailflick assay without any indication of hyperalgesia. Two OFQ/N fragments, OFQ/N (1-7) and OFQ/N (1-11), are active, but far weaker. Blockade of sigma receptors with haloperidol enhances the analgesic potency of spinal OFQ/N, OFQ/N (1-7) and OFQ/N (1-11), but not as dramatically as supraspinal OFQ. Antisense probes targeting the second and third coding exons, but not the first exon, of the cloned mouse OFQ/N receptor (KOR-3) partially block OFQ/N analgesia.
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PMID:Spinal analgesic activity of orphanin FQ/nociceptin and its fragments. 908 86

The cloning of a fourth member of the opioid receptor family has led to the discovery of a new neuropeptide termed orphanin FQ or nociceptin (OFQ/N). Studies in CD-1 mice confirm the ability of OFQ/N to rapidly induce hyperalgesia within 15 min which is insensitive to opioid antagonists. This is followed in the next 30 min by loss of hyperalgesia and the appearance of analgesia in the tailflick assay which is readily reversed by opioid antagonists. However, the very poor affinity of OFQ/N for all the traditional opioid receptors and the insensitivity of OFQ/N analgesia to antisense oligodeoxynucleotides active against MOR-1, DOR-1 or KOR-1 sequences that selectively block mu, delta or kappa1 analgesia, respectively, make it unlikely that OFQ/N analgesia is mediated through typical opioid receptors. Blockade of the antiopioid sigma system by haloperidol enhances the analgesic potency of OFQ/N of more than 100-fold. This effect is pronounced in BALB-C and Swiss-Webster mice. Although OFQ/N alone has little analgesic activity in these mice, the blockade of sigma systems with haloperidol uncovers a robust analgesic response in both strains. Two shorter OFQ/N fragments, OFQ/N(1-7) and OFQ/N(1-11), also are analgesic in CD-1 mice and their actions are reversed by the opioid antagonist diprenorphine despite very poor affinities of both peptides against [125I]OFQ/N binding and all the opioid receptors. In antisense studies, a probe targeting the first coding exon of KOR-3 eliminates OFQ/N hyperalgesia, but not OFQ/N analgesia. Conversely, antisense probes based on the second and third coding exons are inactive against OFQ/N hyperalgesia but readily reverse kappa3 opioid analgesia. These results suggest that OFQ/N elicits both analgesia and hyperalgesia through pharmacologically distinct receptors that do not correspond to traditional opioid receptors.
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PMID:Pharmacological characterization of orphanin FQ/nociceptin and its fragments. 926 52

The present study was designed to observe the effect of orphanin FQ (OFQ, also known as 'nociceptin'), a newly-discovered neuropeptide, on pain behavior and morphine analgesia evaluated by formalin test in rats. It was found that intracerebroventricular (i.c.v.) injection of 0.1 microg OFQ had no effect on formalin-induced pain behavior; but 1, 5, 10 or 20 microg OFQ produced prolonged lifting, licking, biting or shaking of the affected paw with higher pain scoring in dose dependent manner. Repeated i.c.v. injection of antisense olignucleotide (ASO) complementary to OFQ receptor but not mismatch olignucleotide (MSO) resulted in the decrease of pain behavior; in such circumstances, OFQ showed no enhancing effect on formalin nociception. OFQ (0.1 or 1 microg, i.c.v.) significantly attenuated morphine analgesia and ASO could validly antagonize the effect of it. Pretreatment with MSO had no such effect. The present results suggest that OFQ enhances the pain behavior of rat and antagonizes morphine analgesia in formalin test.
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PMID:Orphanin FQ potentiates formalin-induced pain behavior and antagonizes morphine analgesia in rats. 938 90

In mice lacking the nociceptin (or orphanin FQ) receptor gene, when 10 mg/kg of morphine was subcutaneously given, a potent analgesia in the tail pinch test was observed. The analgesic effect of morphine was equivalent among wild-type, heterozygous and homozygous mutant mice. When morphine was given to such mice in a dose of 10 mg/kg once per day for 5 days, wild-type and heterozygous mice showed marked tolerance or reduction in the morphine analgesia on the 5th day, while homozygous mice showed only 50% reduction in the peripheral analgesia of morphine. These findings suggest that nociceptin or its receptor plays important roles in the in vivo mechanism for the development of morphine tolerance.
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PMID:Partial loss of tolerance liability to morphine analgesia in mice lacking the nociceptin receptor gene. 945 34

Homology cloning and, more recently, the sequencing of whole genomes, have identified many open reading frames encoding proteins of unknown function, in particular putative G protein-coupled membrane receptors. Identification of orphan receptors in this way has marked the advent of 'reverse pharmacology' to identify the corresponding physiological ligands. This approach has led to the discovery of the ORL1 (Opioid Receptor-Like 1) receptor, and of its natural ligand, nociceptin/orphanin FQ (noc/oFQ), the basic components of a new peptide-based signalling pathway in the nervous system. Based on genetic criteria, the ORL1 and opioid receptors belong to the same family, as do noc/oFQ and opioid peptides. The marked structural analogy between the ORLI and opioid receptors, especially the kappa-opioid receptor, and the noc/oFQ and opioid peptides, particularly dynorphin A, is not reflected anatomically since noc/oFQ and opioid peptides appear to be located in separate neuronal circuits. Noc/oFQ triggers the same G protein-mediated signalling pathways as do opioids, however, to produce pharmacological effects that sometimes differ from, and even oppose, those of opioids. Noc/oFQ stimulates an outward K+ current and/or inhibits voltage-gated Ca2+ channels, thereby reducing synaptic efficacy, i.e. neuronal activity. In the rat, noc/oFQ is endowed with supraspinal pronociceptive/anti-opioid properties (it suppresses opioid-mediated analgesia), while convergent electrophysiological and behavioural data indicate that the peptide is a spinal analgesic. Noc/oFQ has not yet been found to precipitate withdrawal in morphine-tolerant rats. Nor does it elicit motivational effects, suggesting it lacks abuse liability. Also, by acting supraspinally, noc/oFQ impairs motor performance, suppresses spatial learning, induces feeding, and regulates basal and stress-induced release of pituitary hormones. Noc/oFQ is also active when administered intravenously, exhibiting potent smooth muscle relaxant, diuretic, and antinatriuretic properties. Last but not least, noc/oFQ appears to regulate stimulated immune function, and to be involved in neuronal differentiation. The discovery of noc/oFQ, a neuropeptide with multiple functions, will certainly improve our knowledge of brain physiology, and may find therapeutic applications, for example in the management of pain or hyponatremic and water-retaining diseases. However, given the wide distribution of noc/oFQ and its receptor, the pharmacological profile of noc/oFQ is likely to be incomplete, and other as yet unknown functions of the peptide remain to be discovered. Most helpful in this respect will be the identification of new ligands of the ORL1 receptor, particularly antagonists. If research on noc/oFQ carries on unabated at the present pace, potentially clinically interesting new compounds could become available in the not too distant future.
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PMID:Nociceptin/orphanin FQ and the opioid receptor-like ORL1 receptor. 952 1


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